17beta-hydroxy-4-oxaandrostan-3-ones and derivatives thereof



17fi-HYDROXY-4-OXAANDROSTAN-3-ONES AND DERIVATIVES THEREOF Norman W.Atwater, Arlington Heights, 111., assignor to G. D. Searle & Co.,Chicago, 111., a corporation of Delaware No Drawing. Filed May 22, 1959,Ser. No. 814,964

7 Claims. (Cl. 260-3431) The present invention relates to a new group ofoxasteroids and more particularly to 17fi-hydroxy-4-oxaandrostan-3-one,its 17/8-esters, and its S-Substituted derivatives.

The compounds which constitute this invention are those of thestructural formula on; OR

The radical R is either hydrogen or an acyl radical derived from ahydrocarbon carboxylic acid of less than 8 carbon atoms such as formic,acetic, propionic, valeric, caproic, benzoic and cyclohexanecarboxylicacid and the like. The radical R can be hydrogen, fluorine, chlorine,bromine, or an ether radical such as methoxy, ethoxy, propexy, butoxy,pentyloxy, hexyloxy, benzyloxy or allyloxy.

The compounds of this invention are active pharmacological agents andare active specifically as anabolic and androgenic agents. They are alsoanti-infective agents and are particularly active in preventing thespread of infection caused by cortisone. For example, they prevent thefatal action of Coxsackie virus on mice treated with cortisone.

The compounds of this invention are conveniently prepared from theesters of testosterone by the following reaction sequence. An ester oftestosterone such as the benzoate is ozonized and then treated withhydrogen peroxide to yield the 17-ester of -oxo-l7fi-hydroxy-3,5-seco-A-norandrostan-3-oic acid. treated with at least one equivalent ofan alkali metal borohydride or alkali metal aluminum hydride, e.g.sodium borohydride, at room temperature to yield the 17- ester of17/8-hydroxy-4-oxa-5-androstan-3-one as a mixture of the 511 and 5Bisomers. The Set-isomer is less soluble in methanol and can thus beseparated from the SIB-isomer. The free 17-hydroxy compound can beprepared from the ester by alkaline saponification followed byacidification.

Treatment of the 17-ester of 5-oxo-17 3-hydroxy-3,5-seco-A-norandrostan-3-oic acid with a thionyl halide at room temperatureyields the ester of 17,8-hydroxy-5-halo- 4-oxaandrostan-3-one. TheS-halogen, typically the 5- chloro substituent, can be replaced with analkoxy group by treating with the corresponding alkanol in a base,typically pyridine, to yield the 17-ester of 17B-hydroxy-5-alkyloxy-4-oxaandrostan-3-one. Similarly, the S-benzyl and S-alkenylothers are prepared by use of benzyl alco- 1101 or an alkenol. The free17-hydroxy derivatives of This seco steroid is.

atent C F the invention in spirit or in scope.

7 Patented Feb. 28, 1961 the S-alkyloxy, benzyloxy and alkenyloxysubstituted compounds can be prepared by alkaline saponification.

The invention will appear in further detail from the following exampleswhich are given for the purpose of illustration only and are not to beconstrued as limiting In these examples quantities are given as parts byweight.

Example 1 A solution of 7 parts of 17fl-benzoyloxyandrost-4-en- 3-one inparts of ethyl acetate and parts of acetic acid is cooled to 5 C. Oxygencontaining 3 parts of ozone is passed into the solution during a 45minute period. The solution is allowed to come to room temperature and 5parts of 30% hydrogen peroxide and 15 parts of water are added. Afterstanding for 16 hours, the mixture is diluted with 500 parts of etherand washed thoroughly with water. After exhaustive extraction of theorganic layer with sodium hydroxide, the basic extracts are acidifiedwith concentrated hydrochloric acid and extracted with ether. Theethereal solution is washed with water, dried over anhydrous sodiumsulfate, and distilled under a vacuum to leave a viscous residue whichis recrystallized from a methanol-water mixture and then from isopropylether to give 17B-benzoyloxy-5-oxo-3,5- seco-A-norandrostan-3-oic acidmelting at about 176 C. The optical rotation of the compound is +127.

By equimolar substitution of 17fi-acetoxyandrost-4-en- 3-one or17B-propionoxyandrostl-en-3-one for the 175-benzoyloxyandrost-4-en-3-one in the above process, 17,8-acetoxy-5-oxo-3,S-Seco-A-norandrostan-3-oic acid or 17,3-propionoxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid respectively areobtained.

Example 2 To a solution of 24.7 parts of 17,8-benzoyloxy-5-oxo-2,3-seco-A-norandrostan-3-oic acid in parts of ethanol are added 2.35parts of sodium borohydride in 10 parts of water and 24 parts ofethanol. The mixture is allowed to stand for 90 minutes at roomtemperature after which it is diluted with 800 parts of water. Theresulting mixture is acidified with hydrochloric acid and extracted withether. The ethereal solution is washed with water, dried over anhydroussodium sulfate, and evaporated to yield a residue which isrecrystallized from methanol to yield17fi-benzoyloxy-4-oxa-Sa-androstan-3- one melting at about 207208.5 C.The compound has an optical rotation of +102". The residue obtained onevaporation of the mother liquors yields, on recrystallization from amixture of acetone and isopropylether, 17 8 benzoyloxy 4 oxa5,8-androstan-3-one melting at about 165.5-167.5 C. The compound has anoptical rotation of .+67 and has the structural formula P1] of Byequimolar substitution of 17fi-acetoxy-5-oXo-3,5-seco-A-norandrostan-3-oic acid and 175-propionoxy-5oxo-3,5-seco-A-norandrostan-3-oic acid for the17pbenzoyloxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid in the aboveprocedure, the epimeric pairs of 17/3-acetoxy 4-oxa-5a. and5/8-androstan-3-one and l7B-propionoxy- 4-oxa-5a and 5,6-androstan-3-onerespectively are obtained.

Example 3 To a solution of 1.8 partsof17B-benzoyloxy-4-oxa-5aandrostan-3-one in 85 parts of dioxane, there areadded parts of potassium hydroxide dissolved in 50 parts of water; Themixture is refluxed for 3 hours; poured into 600 parts of water, andacidified with concentrated hydrochloric acid. Upon standing aprecipitateforrns which is recrystallized from ethyl acetate to yieldl'lfi-hydroxy- 4-oxa-5a-andr0stan-3-one melting at about 17-8.5180.5 C.The compound has an optical rotation of +96". It has the structuralformula OH: OH

Example 4 A solution of 1.8 parts of17fl-benzoyloxy-4-oxa-5flandrostan-3-one in 85 parts of dioxane istreated with 5 parts of potassium hydroxide dissolved in 50 parts ofwater. The mixture is refluxed for 3 hours, poured into 600 parts ofwater, and acidified with concentrated hydrochloric acid. Upon standinga precipitate forms which is recrystallized from ethyl acetate to yield17,3- hydroxy-4-oxa-5fi-androstan-S-one melting at about 202- 203 C. Thecompound has an optical rotation of +9".

Example 5 Example 6 A solution of 17fi-hydroxy 4-oxa-Sfi-androstan-S-onein 4.5 parts of benzene, 0.3 part of cyclohexanecarbonyl chloride, and0.5 part of pyridine is allowed to stand for 16 hours at 25 C., and isthen partitioned between ether and Water. The organic layer is washedwith dilute hydrochloric acid and water and dried over anhydrous sodiumsulfate. Upon evaporation of the ether, the residue is recrystallizedfrom methanol to give 1718-cyclohexanecarboxy-4-oxa-5fi-androstan 3 one,melting. at about 203-204 C.

Example 7 After dissolving 1.03 parts of l7e-benzoyloxy-5-oxo-3,5-seco-A-norandrostan-3-oic acid in 9 parts of dry benzene, thesolution is treated with 5 parts of thionyl chloride and allowed tostand for 48 hours at 3 C., While being protected from atmosphericmoisture. The volatile components are then removed by vacuumdistillation and the residue is triturated with cold acetone. The solidresidue is collected and recrystallized from acetone to givel7B-benzoyloxy-5-chloro-4-oxaandrostan-3-one melting at about l8719l C.The optical rotation of this compound is +61".

By equirnolar substitution of thionyl bromide and thionyl fluoride forthionyl chloride in the above example,l7fl-benzoyloxy-5-bromo-4-oxaandrostan-3-one and 17 8- benzoyloxy 5fiuoro-4-oxaandrostan-3-one respectively, are obtained. The latter hasthe structural formula.

CH3 CH3 o-co-cna.

Example 8 A mixture of 0.28 part of 17B-benzoyloxy-5-chloro-4-oxaandrostan-S-one, 4 parts of methanol and 5 parts of pyridine isheated and then allowed to stand for hours at room temperature. Theinsoluble product is collected by filtration and recrystallized fromdichloro-methanemethanol to give17B-benzoyloxy-5-methoxy-4-oxa-androstan-S-one melting at about 238242C. The compound has an optical rotation of +72".

Substitution of 5 parts of ethanol for the methanol used in the aboveexample yields 17B-benzoyloxy-5- ethoxy-4-oxaandr0stan-3-one of thestructural formula Example 9 After dissolving 0.35 part of1718-benzoyloxy-5-chloro- 4-oxaandrostan-3-one in 4.5 parts of allylalcohol and 5 parts of pyridine by heating, the mixture is allowed tostand at room temperature for 72 hours and then poured into parts ofwater. The resulting slurry is extracted with dichloromethane and theorganic layer is Washed with dilute hydrochloric acid and then withWater. The dichloromethane is evaporated to leave a residue which isrecrystallized from dichloromethane-metl'lanol and dichloro-petroleumether to yield 17B-benzoyloxy-5-allyloxy- 4-oxaandrostan-3-one meltingat about l60.5-164.5 C. The compound has an optical rotation of +67".

Example 10 By equimolar substitution of benzyl alcohol for allyl alcoholin the procedure of Example 9 17,8-henzoyloxy-5-,benzyloxyl-oxaandrostan-3-one melting at about 230- 236 C. is obtained.The compound has an optical rotation of +67 What is claimed is: 4. Acompound of the formula 1. A member of the class consisting of thecompounds CH of the structural formula CH 3-0 OH: 3 CH3 0R O 0 o i 0Halogen R 1 5. A compound of the formula CH wherein R is lower alkanoyl,and R is a member of the 6 class consisting of hydrogen, halogen ofatomic weightless than 100, lower alkyloxy, allyloxy and benzyloxy.

2. A compound of the formula CH: CH: o-c

O-(lower alkyl) 6. 17fi-benzoyloxy-5B-allyloxy-4-oxaandrostan-3-one. 00/ 7. 175-henzoyloxy-Sp-benzyloxy-4-oXaandrostan-3-one.

3. 17fl-cyclohexanecarboxy-4-oxa-5p-androstan-3-one. No e erences ci ed.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.2,973,370 6 February 28, 1961 Norman W. Atwater It is hereby certifiedthat error appears in the above numbered patent requiring correction andthat the said Letters Patent. should read as corrected below.

Column 2, line 37, for "2 ,3-seco-" read 3,5sec0- column 4, lines 65 and66, for. dichloro-petroleum" read dichloromethane-petroleum Signed andsealed this 17th day of October 1961.

(SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID L. LADD Commissioner of PatentsUSCOMM-DC

1. A MEMBER OF THE CLASS CONSISTING OF THE COMPOUNDS OF THE STRUCTURALFORMULA